Abstract
It has now been widely accepted as “Glutamate Hypothesis of Schizophrenia” that disturbed neurotransmission via the N-methyl-D-aspartate type glutamate receptor may be implicated in the pathophysiology of schizophrenia, because (1) competitive and non-competitive antagonists of the NMDA receptor cause schizophrenia-like positive and negative symptomatologies, (2) the rank order potency of schizophrennomimetic effects of NMDA receptor antagonists is closely correlated with that of their NMDA receptor-current blocking efficacies, and (3) schizophrenic patients have been reported to be more sensitive to psychotomimetic actions of NMDA antagonists than healthy volunteers. The fact that selective elimination of endogenous D-serine attenuates NMDA receptor functions in mammalian brains suggests that dysregulation of the extracellular contents of D-serine could be a candidate mechanism for the possible NMDA receptor dysfunction. The induction of current pharmacotherapy-resistant symptoms by NMDA receptor antagonists leads to the idea that NMDA receptor-D-serine system could be a suitable target for further analysis of the pathophysiology and development of novel pharmacotherapy for schizophrenia. Therefore, in this article, we are trying to overview the present status of understanding of the molecular and cellular mechanisms underlying release and uptake of D-serine and their controls. Future applications of these findings to drug discovery for intractable schizophrenic symptoms are also discussed.
